Enantioselective Generation of Adjacent Stereocenters in a Copper‐Catalyzed Three‐Component Coupling of Imines, Allenes, and Diboranes

Abstract A highly enantio‐ and diastereoselective copper‐catalyzed three‐component coupling affords the first general synthesis of homoallylic amines bearing adjacent stereocenters from achiral starting materials. The method utilizes a commercially available NHC ligand and copper source, operates at ambient temperature, couples readily available simple imines, allenes, and diboranes, and yields high‐value homoallylic amines that exhibit versatile amino, alkenyl, and boryl units.

achiral building blocks are rare, and typically use exotic imines. [3,4] This is likely due to the difficulty in forming isomerically defined allyl nucleophiles [5] and the low reactivity [6] and possible E/Z geometries of the imine coupling partner, [7] all of which affect the regio-and stereoselectivity during the subsequent coupling event.
To keep apace with the demands of modern synthetic chemistry, multicomponent reactions must address challenging couplings in which numerous stereocenters are installed selectively: [8] If complex chiral products could be assembled from several readily available achiral components in a onepot process, then diverse collections of high-value compounds could be quickly constructed by simple variation of the material inputs. In recent times, enantioselective multicomponent couplings with allenes have provided efficient methods for the synthesis of highly functionalized homoallyl stereocenters. [9] For example, the coupling of allenes and diboranes [10] with aldehydes or ketones [11] and allylic electrophiles [12] has been explored. [13][14][15][16] However, application to the synthesis of chiral non-racemic homoallylic amines has been surprisingly scarce, [17,18] given their importance, and this is likely due to the poor reactivity of imines. [6,7] Morkens seminal report is the only example of an enantioselective multicomponent reaction coupling allenes, imines, and B 2 pin 2 (Scheme 1 B). [19] The palladium-catalyzed process utilizes a TADDOL phosphoramidite ligand, and initial asymmetric diboration [13c] of the allene component furnishes allylic boronic esters that are subsequently coupled with imines. The resultant highly enantiomerically enriched linear homoallylic amines were then oxidized and acylated to form isolable b-amino ketones. However, if a process could be developed that employs a low-cost metal and a commercially available ligand, as well as utilizing a convergent assembly of readily available achiral starting materials to generate homoallylic amines bearing adjacent stereocenters, it would be a significant advance in the synthesis of such high-value products.
We next examined the allene component of the reaction (Scheme 4). 1-Substituted allenes bearing primary and more hindered secondary alkyl groups gave the expected coupling products in universally high enantioselectivity (! 93:7 e.r.). Alkyl substituents bearing no substitution (3 m), a silyl ether (3 n), a free alcohol (3 o), or a phenyl group (3 p), were tolerated.
We also explored various nitrogen substituents on the imine by incorporating medicinally relevant and functionalizable motifs (Scheme 5). Methyl ester (3 x), 5-quinolinyl (3 y), morpholino (3 z), and (pinacolato)boryl (3 aa) moieties were successfully incorporated into the coupling products. To further probe the utility of the asymmetric three-component coupling, we employed Procaine, a classic local anesthetic, [27] in imine formation. Procaine was condensed with o-tolualdehyde and submitted to the standard conditions for the enantioselective three-component coupling. The complex homoallylic amine 3 ab was obtained in 30 % yield (2 steps) in 94:6 d.r. and 96:4 e.r. It is interesting to note that basic nitrogen atoms, moieties that are often avoided in synthetic methodology, are well tolerated by the copper-catalyzed process (3 y, 3 z, and 3 ab).
Single-crystal X-ray crystallography of 3 w revealed its R configuration. [28] Analysis of the X-ray crystal structures of complexes of Kündigs C 2 -symmetric ligands [24,25,29] with other metals has allowed us to propose a model for the stereochemical outcome of the enantioselective three-component coupling reaction where the flanking naphthyl rings allow approach of the imine towards the allyl copper species from one face (Scheme 6). The anti selectivity arises from a sixmembered-ring chair transition state. [17i] Finally, the scalability of the process was assessed. Using just 1.0 mol % of CuI and 1.1 mol % of ligand precursor 6, 1 g of imine 1 a was converted into 2 g of product 3 a, with high levels of efficiency and selectivity (98 %, > 95:5 d.r., 99:1 e.r.; Scheme 7).
To demonstrate the synthetic utility of products 3, we oxidized 3 a under standard H 2 O 2 /NaOH conditions and obtained b-amino ketone 7, which bears a-and b-stereocenters, in high yield (82 %) and importantly without erosion of the stereochemical integrity (> 95:5 d.r., 98:2 e.r.; Scheme 7). The BÀN interaction present in the products of the coppercatalyzed three-component coupling make them particularly amenable to highly stereoselective manipulation. For example, by simply using Pd/C, 3 a underwent a substrate-controlled highly stereoselective hydrogenation, and gave secondary boronic ester 8, which exhibits three contiguous stereocenters (54 %, > 95:5 d.r., > 99:1 e.r.). [30] Scheme 4. Variation of the allene in the enantioselective coppercatalyzed three-component coupling. The d.r. values were determined by 1 H NMR analysis of the crude reaction mixtures. The e.r. values were determined by HPLC analysis on a chiral stationary phase.
[a] See Scheme 3 for the reaction conditions. [b] Conditions as in Scheme 3, but with imidazolium salt 5 at À15 8C. [c] Conditions as in Scheme 3, but with B 2 pin 2 (2 equiv), CuI (10 mol %), 6 (11 mol %), and t BuOK (2 equiv). TBS = tert-butyldimethylsilyl. Scheme 5. Synthetically and medicinally relevant functional groups in the imine nitrogen substituents: Enantioselective copper-catalyzed approach to complex homoallylic amines. The d.r. values were determined by 1 H NMR analysis of the crude reaction mixtures. The e.r. values were determined by HPLC analysis on a chiral stationary phase.
[a] See Scheme 3 for the reaction conditions. Scheme 6. Model for the stereochemical outcome of the coppercatalyzed enantioselective three-component coupling of imines, allenes, and diboranes.
Scheme 7. Gram-scale enantioselective three-component coupling, and oxidation and reduction of 3 a.
In conclusion, we have developed the first general method for the enantioselective and diastereoselective synthesis of homoallylic amines containing adjacent stereocenters from achiral starting materials, utilizing an unprecedented sequence of allene borocupration followed by allyl cupration of imines. The active allyl metal intermediate is formed in situ concurrent with CÀB bond formation; therefore, prefunctionalized allyl metal derivatives are not required, and simple allenes can be used. The process exploits a low-cost, commercially available copper(I) salt and chiral NHC catalytic system and readily available imines, allenes, and diboranes to forge molecules bearing versatile amino, alkenyl, and boryl motifs at ambient temperature. The reaction tolerates a broad range of functional groups, including basic amines. We have demonstrated the versatility of the method through a late-stage asymmetric functionalization of Procaine, and in easily elaborating our products to b-amino ketones and boronic esters bearing three contiguous stereocenters.